Safety and tolerability of pardoprunox, a new partial dopamine agonist, in a randomized, controlled study of patients with advanced Parkinson's disease.

AIMS: To investigate the safety and tolerability of pardoprunox (SLV308), a novel partial dopamine agonist, as an adjunct to levodopa in patients with advanced Parkinson's disease, using two titration schedules. METHODS: Patients were randomized to pardoprunox (n = 51) or placebo (n = 11). Pardoprunox was titrated to the highest tolerated dose (range, 0.3-42 mg/day) over 7 weeks, using a gradual dose escalation without intermediate steps (group 1) or with intermediate steps (group 2). RESULTS: The cumulative drop-out rate was greater in group 1 (without intermediate steps, 56.0%) than in group 2 (with intermediate steps, 34.6%), or with placebo (9.1%). In group 2, doses up to 18 mg/day were well tolerated with a cumulative drop-out rate of 7.7% (2/26) and a drop-out rate due to adverse events of 4.0% (1/26). The most common adverse events reported were nausea, vomiting, headache, and dizziness. There was a trend for reduced OFF time (p = 0.054) in the combined pardoprunox group compared to placebo. CONCLUSIONS: The pardoprunox safety and tolerability profile as an adjunct to levodopa was improved using a gradual titration schedule that included intermediate dose steps. Using this titration, doses up to 18 mg/day were well tolerated.

Antibiotic use after cefuroxime prophylaxis in hip and knee joint replacement.

The amount of additional antibiotics measured by defined daily dose (DDD) methods after 2651 hip and 362 knee replacements was assessed after prophylaxis with one or three doses (1502/1511 patients) of cefuroxime. No differences were observed between the two regimens with respect to total amount, type, indication, and duration of additional antibiotics. The incidence of joint sepsis did not differ significantly between the two trial arms, but the sample was too small for definite conclusions. There were 11.4 DDD/100 bed days of additional antibiotics used in 21% of patients after hip replacement and 15.7 DDD/100 bed days in 31% after knee replacement. For wound problems, 3.8 and 6.9 DDD/100 bed days were given in the hip- and knee-replacement groups. For distant infection, 6.5 DDD/100 bed days was administered in both groups. Duration of therapy varied only in relation to indication. Prescribed were penicillins (43% to 50%), sulfonamides (18%), cephalosporins (10% to 16%), and nitrofurantoin (8% to 13%); drug use was related to the type of infection.

Effectiveness in inhibition of recovery of cell survival by cisplatin and carboplatin: influence of treatment sequence.

Clinical protocols have been designed to combine platinum-based drugs and radiation in the treatment of cancer. The rationale for this approach has been developed from preclinical studies demonstrating that platinum compounds can potentiate the cytotoxic effects of radiation toward cells. In the present study multicellular spheroids derived from squamous cell carcinoma cell line HN-1 have been used to study the effects of both cisplatin and carboplatin when administered prior to, concurrently, and after irradiation treatment. To study the influence of platinum compounds on sublethal damage repair, single and split doses of radiation were applied. Growth delay and proportion cured spheroids served as endpoints. Both cisplatin and carboplatin had no potentiating effect when administered 24 hr prior to irradiation. When administered 3 hr after completion of irradiation procedures, growth delay after single and split doses were enhanced to the same extent. The drug enhancement ratio for cisplatin was larger (1.5) than for carboplatin (1.2). Both single and split doses were enhanced by the same factor, which was interpreted as no effect on sublethal damage repair. When platinum compounds were present in the target cells at the time of irradiation, especially the split dose radiation response was strongly enhanced: the drug enhancement ratio was 3.9 for cisplatin and 3.2 for carboplatin. Recovery from sublethal damage was totally repressed. This study shows that platinum compounds can potentiate radiation and that for maximum effect the sequence of the two treatment modalities is of utmost importance. Moreover, these results may in part explain the heterogeneous outcomes of trials combining platinum compounds and radiation.

Repair of sublethal damage in two human tumor cell lines grown as multicellular spheroids.

Multicellular tumor spheroids (MTS) provide a suitable in vitro model to study radiation sensitivity of tumor cells. Two cell lines of human origin, obtained from a neuroblastoma (NB-100) and a squamous cell carcinoma (HN-1), were exposed to graded doses (4-9 Gy) of radiation with 18 MV photons. Radiation was applied either as a single or as a split dose with an interval of 6 hr to determine the extent of sublethal damage repair. Treated spheroids regrew at approximately the same growth rate as control multicellular tumor spheroids, preceded by a static or regression phase. Radiation response was quantified in terms of regrowth delay, expressed as the time needed for treated spheroids to obtain an 8-fold increase of the initial volume at the time of irradiation. Data obtained from regrowth delay analysis were used to calculate the extent of sublethal damage repair, showing for the squamous cell carcinoma line a fractionally higher capacity to repair sublethal damage than the neuroblastoma line. Repair increased with larger dose fractions in both cell lines. Our results show that multicellular tumor spheroids from the two cell lines used in this study are best applicable at relatively high total radiation doses. This makes multicellular tumor spheroids a suitable model for the in vitro evaluation of clinical treatment rationales such as hyperfractionation.

Radiosensitivity of different human tumor cells lines grown as multicellular spheroids determined from growth curves and survival data.

Five human tumor cell lines were grown as multicellular tumor spheroids (MTS) to determine whether multicellular tumor spheroids derived from different types of tumors would show tumor-type dependent differences in response to single-dose irradiation, and whether these differences paralleled clinical behavior. Multicellular tumor spheroids of two neuroblastoma, one lung adenocarcinoma, one melanoma, and a squamous cell carcinoma of the oral tongue, were studied in terms of growth delay, calculated cell survival, and spheroid control dose50 (SCD50). Growth delay and cell survival analysis for the tumor cell lines showed sensitivities that correlated well with clinical behavior of the tumor types of origin. Similar to other studies on melanoma multicellular tumor spheroids our spheroid control dose50 results for the melanoma cell line deviated from the general pattern of sensitivity. This might be due to the location of surviving cells, which prohibits proliferation of surviving cells and hence growth of melanoma multicellular tumor spheroids. This study demonstrates that radiosensitivity of human tumor cell lines can be evaluated in terms of growth delay, calculated cell survival, and spheroid control dose50 when grown as multicellular tumor spheroids. The sensitivity established from these evaluations parallels clinical behavior, thus offering a unique tool for the in vitro analysis of human tumor radiosensitivity.

Radiosensitivity of human melanoma spheroids influenced by growth rate.

The radiosensitivity of human melanoma cell line BRO was investigated using the multicellular tumor spheroid system. By adding different concentrations of bovine serum to the tissue culture medium, two different growth rates could be obtained. Spheroids (200-250 microns) were irradiated with graded single doses of X rays (2-8 Gy). The radiation response was quantified using specific growth delay, clonogenic cell survival, and spheroid cure. All three assays showed a growth rate dependent radiation response. At both growth rates the spheroid growth fraction and critical cell number were of comparable magnitude. There was a strong correlation between the radiation response of spheroid regenerating units and clonogenic cells from dispersed spheroids. Cell survival curves indicated a decreased ability to accumulate sublethal damage in fast growing multicellular tumor spheroids. From this study it appears that the intrinsic radiosensitivity of human melanoma cell line BRO cells in multicellular spheroids is modulated by intratumoral conditions.

Skin vascular reactivity in healthy subjects: influence of hormonal status.

To investigate the influence of the hormonal status on skin vascular reactivity, 18 males, 18 women using oral contraceptives (oc), 17 premenopausal, and 18 postmenopausal women were studied. Finger skin temperature (FST, in degrees C) and laser Doppler flux (LDF, in perfusion units) were measured during heating (45 degrees C water bath) and cooling (15 degrees C) followed by a subsequent recovery period. Maximal heat-induced vasodilation was significantly higher in women using oc and in premenopausal women when compared with males. During cooling, FST and LDF were significantly higher in males compared with women using oc and premenopausal women, respectively. FST was also higher in postmenopausal women than in women using oc. During recovery, FST and LDF were significantly higher in males than in women using oc, and LDF was also higher in males than in premenopausal women. These findings are consistent with a less pronounced and less prolonged cold-induced vasoconstriction in males. Other hemodynamic (blood pressure or heart rate) or biological factors (age, amount of subcutaneous fat, hand volume, or body mass index) that possibly influence peripheral blood flow were found not to influence the results. The observed differences in vascular reactivity toward temperature changes between subjects with a different hormonal status suggest that sex hormones influence finger skin perfusion.

Urinary excretion of prostaglandins during infancy and childhood: influence of age, sodium restriction and posture.

The influences of age, sodium restriction and posture on 24-hour urinary excretion of prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF 2 alpha), 6-keto-prostaglandin F1 alpha (6-keto-PGF 1 alpha) and thromboxane B2 (TXB2) were investigated in 111 healthy children and youngsters in the age between 1 day and 16 years. A considerable degree of variation was found in normal 24-hour urinary prostaglandin excretion in all age groups. There was no significant effect of age on the urinary excretion of prostaglandins when data were corrected for body surface area. In addition, sodium restriction and posture had no influence on the excretion of PGE2, PGF 2 alpha, 6-keto-PGF 1 alpha and TXB2. Our results indicate that in the first days of life the kidney already has the capacity to synthesize prostaglandins in amounts comparable to older children.

Urinary polyamine and metabolite excretion by children with Zellweger's syndrome.

In order to investigate whether, due to a lack of peroxisomes, polyamine degradation is altered in patients with the cerebro-hepato-renal syndrome of Zellweger, we determined total, free and acetylated polyamines and some of their catabolites in urines of six patients and age-matched healthy children. The normal polyamine excretion patterns of the patients, compared to the control group, suggest that either the intracellular localisation of the polyamine degrading enzyme, polyamine oxidase, is not exclusively limited to peroxisomes or that the enzyme is located in the peroxisomal matrix.

Reference values for amino acids in cerebrospinal fluid of children determined using ion-exchange chromatography with fluorimetric detection.

One thousand specimens of CSF were collected from subjects ranging in age from newborn to 18 yr, who were undergoing a diagnostic lumbar puncture. Sixty-two samples were judged retrospectively as being suitable for calculating reference age-related values. The analyses were performed by an amino acid analyser using ion-exchange chromatography with fluorimetric detection giving a tenfold increase in sensitivity, thereby enhancing the diagnostic capabilities. As many as 36 known compounds could be detected, additionally 10 we could not identify. In children older than 3 yr nine of the identified compounds showed age-dependency. We found 22 amino acids to be significantly higher in infants younger than 1 yr, with only gamma-aminobutyric acid being significantly lower in infants. Alpha-aminoadipic acid showed a sex difference, being slightly higher in girls.

The effect of familiality on clinical presentation and survival in mammary carcinoma.

In a series of 467 patients treated for mammary carcinoma 96 (20%) had a family history for this tumour. Sixty-eight (71%) had at least one first degree, 28 (29%) a second or third degree family member. Only the mean age of the second degree relative group differed significantly from that of the non-familial group. The size of the primary tumour at first presentation did not differ significantly in the familial and non-familial group, as the estimated survival. So patients with a family history for mammary carcinoma did not present themselves in an earlier stage of disease. Because of the higher risk of developing this type of tumour in female relatives we have to instruct this potential patient group more explicitly.

Effectiveness of cis-platin and carboplatin in the chemotherapy of squamous cell carcinoma grown as multicellular spheroids.

We compared cis-platin (DDP) and its analogue, carboplatin (JM8, CBDCA) in their ability to inhibit spheroid growth. The activities of DDP and JM8 were also compared in an antimetabolic assay for their ability to inhibit (3H)-thymidine incorporation in multicellular tumor spheroids. The spheroids were derived from a squamous cell carcinoma cell line HN-1, originally derived from a tumor of the tongue. To produce equal levels of growth delay in spheroids, carboplatin was required at concentrations approximately 16 times that of DDP. Carboplatin also required much longer incubation periods than DDP to produce equivalent growth delay and proportions of cured spheroids. Reflecting the initial response to chemotherapy, the antimetabolic assay showed that carboplatin was required at higher concentrations and longer exposure times to produce equal inhibition of the nucleotide precursor thymidine. These findings may have implications for the clinical use of these drugs and in particular would support a role for carboplatin in the treatment of squamous cell carcinoma of the head and neck, since total free-drug exposure of patients to carboplatin may be up to 16-fold greater than with DDP, and the clinical side effects of carboplatin have been shown to be well tolerated. However, one must be cautious about applying in vitro data to clinical situations.

The effects of CTR-24, a biphasic oral contraceptive combination, compared to Diane-35 in women with acne.

One-hundred-and-eighty-three women were enrolled in an open, randomized, multicentre study in which the effects on acne of a low-dose biphasic oral contraceptive containing a daily dosage of 25 micrograms desogestrel and 40 micrograms ethinylestradiol (7 days) and a daily dosage of 125 micrograms desogestrel and 30 micrograms ethinylestradiol (15 days) were compared to Diane-35 containing a daily dosage of 2.0 mg cyproterone acetate and 30 micrograms ethinylestradiol (21 days) during four cycles of treatment. Clinical and photographic evaluation of acne plus laboratory assessments were done before treatment and at the end of cycle 4. A reduction with regard to the number of lesions and the degree of severity was observed in both groups. No differences were found between the two treatments in the clinical and photographic evaluation. In both treatment groups, a decrease in total testosterone and 3 alpha-17 beta-androstanediol glucuronide was observed and an increase in SHBG. The decrease in 3 alpha-17 beta-androstanediol was statistically significantly more pronounced in the Diane-35 group.

The effects of acute cerebrovascular disease on serum and cerebrospinal fluid parameters.

In order to evaluate the effects due to acute cerebrovascular disease on serum and cerebrospinal fluid (CSF) parameters, biochemical data from 312 patients were studied. In serum, CK, LD and alpha 1 protein fraction showed a moderately close relationship to the severity of stroke. In CSF there could not be observed any relation between enzymatic activities (LD, ASAT, CK) and the severity of the disease. The same result was found for CSF protein and the ratio CSF albumin/serum albumin, parameters which are indicative for Blood Brain Barrier (BBB) disturbances. Substances from the intermediate metabolism in the Central Nervous System (CNS) (lactate and pyruvate) were evidently raised in CSF and there was a clear relation between the CSF concentration and the severity of stroke. No indication for IgG immunoglobulin abnormalities in CSF was found. The concentration of neurotransmitter metabolite 5HIAA in CSF was significantly higher in (in)completed stroke than in Transient Ischaemic Attack.

Peritoneal transport kinetics of glucose, urea, and creatinine during infancy and childhood.

Peritoneal handling of glucose and metabolites is reported to be higher in young children treated with CAPD than in older children. Reference curves for the standardized peritoneal equilibration test (PET) are not available for younger ages. The present study describes the results of the PET in 19 children (mean age 5.0 years, ranging from 0.3-15) during the first month of CAPD treatment. No age dependency for the handling of glucose, urea, and creatinine could be established when the group was subdivided into 1. children below the age of 3 years, and 2. children above that age. There was, however, a significant correlation between equilibration of creatinine and age, indicating more rapid equilibration at younger ages.

[Echography of the normal kidney in infants]. / Echografie van de normale nier bij de zuigeling.

In 33 infants from 0 to 11 months old, apparently without urinary tract disease, the kidneys were examined sonographically. Renal length was correlated with age and bodyweight. The renal echopattern was studied: Normal kidneys in newborn and young infants have several distinct sonographic features: the renal cortex is more echogenic, the medullary pyramids are prominent and relatively anechoic, the central sinus echo is reduced. This pattern occurs until the age of 3 months and changes to the adult pattern at the age of 5 months.

Pardoprunox as adjunct therapy to levodopa in patients with Parkinson's disease experiencing motor fluctuations: results of a double-blind, randomized, placebo-controlled, trial.

AIMS: To determine the efficacy and safety of pardoprunox in levodopa-treated patients with Parkinson's disease (PD) experiencing motor fluctuations. METHODS: Patients were randomized to pardoprunox (up to 42 mg/day, n = 150) or placebo (n = 144). Pardoprunox was titrated to an optimal dose over 7 weeks, followed by a 12-week stable dose period. The primary efficacy variable was the change from baseline to study endpoint in total daily OFF time, based on patient diaries. Secondary analyses included the change in ON time without troublesome dyskinesias, UPDRS-ADL + Motor ON, UPDRS-ADL OFF and PDQ-39. Subgroup analyses explored the impact of pardoprunox on dyskinesias (UPDRS items 32 + 33), depression (Hospital Anxiety Depression Scale) and pain (Visual Analogue Scale). RESULTS: Pardoprunox significantly reduced OFF time versus placebo (-1.62 h/day versus -0.92 h/day, respectively, p = 0.0215). Compared to placebo, pardoprunox improved ON time without troublesome dyskinesias (p = 0.0386), UPDRS-ADL + Motor ON (p = 0.0003), and UPDRS-ADL OFF (p < 0.0001), while no significant difference was observed on PDQ-39. A high drop-out rate due to adverse events (AEs) (pardoprunox, 37%; placebo, 12%) suggested that the selected dose range may have been too high, and/or titration was too rapid. CONCLUSIONS: Pardoprunox decreased OFF time and increased ON time without troublesome dyskinesias in levodopa-treated PD patients. The high drop-out rate at the selected doses justifies the investigation of lower doses. The impact of pardoprunox on dyskinesias and non-motor symptoms deserves further investigation.

Improvement of lesion detection by echographic image processing: signal-to-noise-ratio imaging.

Signal-to-noise-ratio (SNR) images were constructed by a sliding window technique. Theoretical derivations of the first order statistical properties of SNR images are given for the case of intensity coding of the original images for low number densities and for the limit case of fully developed speckle. The original images were obtained by realistic simulations of backscattering by homogeneous media, while using a range of number densities of the scatterers (isotropic scattering). The SNR imaging method is illustrated by results obtained from simulated scattering media containing a lesion that is contrasting in reflectivity level or in number density of the scatterers. A considerable improvement in lesion detection is obtained if the primary difference from the background speckle is due to a different number density of the scatterers within the lesion.

Cefuroxime for prevention of postoperative coxitis. One versus three doses tested in a randomized multicenter study of 2,651 arthroplasties.

Infection prophylaxis in hip replacement with one perioperative dose of cefuroxime was evaluated in a randomized controlled multicenter study using a three-dose regimen as a control. All the operations were performed in conventionally ventilated operating theaters. Of the 2,796 hip replacements entered in the study, 145 replacements were excluded because of protocol violations. The remaining 2,651 hip replacements were analyzed: 1,327 and 1,324 in the one- and the three-dose group, respectively. There were no differences between the one-dose and the three-dose groups as regards the incidence of postoperative wound-healing problems, and urinary tract or other distant infections. The use of additional antibiotics after the perioperative prophylaxis did not differ between the treatment groups. After a mean follow-up period of 13 months, joint sepsis was diagnosed in 11 of the patients in the one-dose group (0.83 percent) and in 6 of the patients in the control group (0.45 percent). This difference was not significant. Because the estimated difference between the one-dose and the three-dose group was 0.38 percent, we could not confirm that the efficacy of one dose was equal to three doses. An extended follow-up study, with more cases of joint sepsis, may provide more conclusive data. Until then, a three-dose regimen is recommended.

Sublethal damage repair in two radioresistant human tumor cell lines irradiated as multicellular spheroids.

Melanoma and lung adenocarcinoma may be amenable for radiotherapy if it were possible to increase the presently used total dose. In order to investigate this, spheroids from two cell lines of human origin, one obtained from a BRO melanoma and one from an NCI-H125 lung adenocarcinoma were exposed to graded doses (3-9 Gy) of radiation with 18-MV photons. Radiation was applied either as a single dose or as split doses with an interval of 6 h to determine the extent of sublethal damage repair. Radiation response was quantified in terms of spheroid cure and specific growth delay. Both cells lines have previously been shown to be less sensitive than a neuroblastoma and a squamous cell carcinoma cell line grown as spheroids. Data obtained from the growth delay analysis were used to calculate the extent of split-dose recovery. Repaired dose for BRO spheroids did not increase after 7 Gy, whereas in NCI-H125, the repaired dose showed a steady increase. Recovery ratios did not differ between the two cell lines, but were lower than reported for normal tissues. Both cell lines revealed a low repair capacity was expressed by the beta-value of the linear-quadratic (LQ) equation. However, repair capacity for sublethal damage as expressed by the dose repaired and the beta-value of the LQ equation was not different from values reported earlier by us for neuroblastoma and squamous cell carcinoma when grown as spheroids. This indicates that the low radiosensitivity for the cell lines used in this study is determined by the alpha-value of the LQ equation. Our results support the clinical finding that the application of increased total radiation doses in the treatment of melanoma and lung adenocarcinoma may be feasible if radiation is applied in multiple small fractions to ensure normal tissue sparing.